BCL2L1 (BCL-XL) and MCL1 are frequently amplified in solid tumors, including NSCLC. The addiction of NSCLC to BCL-XL or MCL-1 has been demonstrated by genetic and molecular approaches targeting these molecules. Although ABT-263, the current best small-molecule BCL-2/BCL-XL inhibitor, has demonstrated clinical efficacy in BCL-2-driven tumors, such as chronic lymphocytic leukemia, it has very limited activity in solid tumors, partially due to its less effectiveness in antagonizing BCL-XL in cellula context. Therefore, there is a critical need for novel small-molecules that can effectively antagonize cellular BCL-XL and/or MCL-1 for the development of highly effective cancer therapeutics. The objective of this application is to determine the therapeutic potential of BM-1197, a recently discovered highly potent small-molecule BCL-XL/BCL-2 inhibitor, for the treatment of NSCLC. The central hypothesis is that BM-1197 possesses strong antitumor activity as a single-agent against a subset of NSCLC addicted to BCL-XL, and exhibits a much broader antitumor activity in NSCLC when combined with drugs that can neutralize MCL-1. This hypothesis is based on the exciting preliminary studies, which show that BM-1197: (1) effectively induces apoptosis by targeting BCL-XL and BCL- 2 in a variety of cell line models; (2) achieves complete and persistent tumor regression in tumor xenograft models even with weekly dosing; (3) causes transient platelet reduction in mice, but otherwise is well-tolerated; (4) exhibits potent inhibitory activity in NSCLC cell lines with amplified BCL2L1; (5) achieves strong synergy with docetaxel and the recently FDA-approved MEK inhibitor trametinib in a significant proportion of NSCLC cell lines; and (6) in direct comparison, is more potent in vitro and more efficacious in vivo than ABT-263. To achieve the ultimate goal of developing BM-1197 as a new, effective, and personalized medicine for NSCLC, three specific aims will be pursued: 1) determine the antitumor activity of BM-1197 as a single agent in NSCLC in vitro and in vivo and identify the molecular determinants for its sensitivity; 2) determine the mechanism of action, antitumor activity, and potential toxicity of BM-1197-docetaxel combination in NSCLC in vitro and in vivo; and 3) determine the mechanism of action, antitumor activity, and potential toxicity of BM-1197-trametinib combination in NSCLC in vitro and in vivo. Multiple complementary preclinical models, including a large panel of well-characterized NSCLC cell lines, cell lined-derived xenografts, and patient-derived xenografts of NSCLC in mice will be employed. This project is expected to establish the strong antitumor activity of BM-1197 in complementary preclinical models of NSCLC and identify key molecular determinants for the sensitivity of BM- 1197 in the settings of single agent and combinations. BM-1197 is undergoing IND-enabling studies and will enter clinical trials shortly. Therefore, the success of this project will have a significant impact for translation of BM-1197 into a new therapy for NSCLC. Identifying the molecular determinants for the sensitivity of BM-1197 will greatly facilitate the development of BM-1197 as a novel personalized therapy for NSCLC.